Genetic Linkage in Lupus

项目摘要 目前已有124种出版物为系统性红斑狼疮的遗传学研究建立了185个疾病风险基因。 (SLE)具有强劲的支持数据。这与AI0274717启动33年时的情况完全不同 作为对基因连锁的搜索。现在，除了185个风险基因外，我们还有强有力的间接证据 EB病毒(EBV)在SLE起源中的病因学作用，特别是考虑到最近发表的 含有潜伏期III的转录复合体在基因组中的位置之间有很强的关联性 基因产物EB病毒核抗原2(EBNA2)与系统性红斑狼疮的遗传易感基因。这个协会有 已被证实并推广到目前已知的SLE危险基因座。此外，新数据显示，EBNA3C 和EBNALP，都是EBV潜伏期III基因产物，也强烈集中在SLE风险基因座，所有 EBNA2，-3C，&-LP，聚集在一起，并在聚合中间接结合到一半以上的已知 系统性红斑狼疮风险基因座。一组人类转录因子和辅助因子(TF)倾向于在这些相同的SLE风险下结合DNA 精神错乱。我们的假设是，许多导致系统性红斑狼疮的遗传机制在EBV转化的B细胞中起作用， 由于EBV潜伏期III基因的表达。由于185个风险基因座中约90%的可信因果变异 都在基因组区域，预计具有调节功能；因此，转录因子的作用有望是重要的 在系统性红斑狼疮的遗传机制中。缺少的是对目标的识别，这是我们知识中的一个严重差距 受这些风险变量调控的基因。考虑到潜伏期III基因意想不到但占主导地位的影响 与系统性红斑狼疮风险基因相关的产品，我们得出结论，开始系统性红斑狼疮的细胞类型 寻找与疾病相关的靶基因是EBV感染和转化的B细胞。在目标1中，我们将专注于 特别注意在这些细胞中识别尽可能多的系统性红斑狼疮风险基因的靶基因 重点关注EBNA2的参与。在目标2中，我们将集中于目标基因的等位基因差异 SLE风险基因座变异的风险和非风险等位基因诱导的表达，同样要特别注意 EBNA2的可能作用。 我们有初步数据支持我们执行所提议的实验的技术能力，并已 构建了执行拟议实验所需的许多试剂，这些实验已经启动。我们 将采用高通量系统生物学方法筛选和探索185个基因座的基因调控 为评价EBNA2在SLE病因学相关调控中的作用奠定基础。非同寻常的新事物 商业上可用的方法将使拟议的筛查程序实用、可行和负担得起。 如果我们的假设是正确的，并且我们在风险中证明了EBNA2依赖的基因调控机制 因此，这些可能是SLE发生的潜在原因机制。这些结果将 为重要的下一步奠定基础，以改变风险的方式扰乱已确定的机制 发展成系统性红斑狼疮或改变疾病的持续能力。

Project Abstract There are 124 publications that establish 185 disease risk loci for the genetics of systemic lupus erythematosus (SLE) with robust supporting data. This is a completely different situation than when AI0274717 started 33 years ago as a search for genetic linkage. Now, in addition to the 185 risk loci we have strong circumstantial evidence for an etiologic role for Epstein-Barr virus (EBV) at the origin of SLE, especially considering the recently published powerful association between the location in the genome of transcription complexes containing the Latency III gene product, Epstein Barr Nuclear Antigen 2 (EBNA2) and the genetic risk loci of SLE. This association has been confirmed and extended to the at present known SLE risk loci. In addition, new data show that EBNA3C and EBNALP, both also EBV Latency III gene products, are also powerfully concentrated at the SLE risk loci, all three, EBNA2, -3C, & -LP, clustering together and in aggregate binding indirectly to more than half the known SLE risk loci. A set of human transcription factors and co-factors (TFs) tend to bind DNA at these same SLE risk loci. Our hypothesis is that many genetic mechanisms that cause SLE operate in the EBV transformed B cell, because of the EBV Latency III gene expression. Since ~90% of the plausibly causal variants in the 185 risk loci are in genomic regions, predicted to have regulatory function; therefore, the role of TFs promises to be important in the genetic mechanisms of SLE. What is missing, a serious gap in our knowledge, is the identify of the Target genes regulated by these risk variants. Given the unexpected, but dominating influence of the Latency III gene products in associations with the SLE risk loci, we conclude that the cell type in which to begin the systematic search for the disease relevant Target genes is the EBV-infected and transformed B cell. In Aim 1 we will focus on identifying Target genes in these cells for as many of the 185 SLE risk loci as possible with special attention focused on the involvement of EBNA2. In Aim 2 we will concentrate on the allelic differences in Target gene expression induced by the risk and non-risk alleles of SLE risk locus variants, again with special attention to the possible role of EBNA2. We have preliminary data that support our technical capacity to perform the experiments proposed and have constructed many of the reagents needed to perform the proposed experiments, which have been initiated. We will adapt high throughput systems biology methods to screen and explore the gene regulation of the 185 loci to build a foundation to evaluate the role EBNA2 has in SLE etiology relevant regulation. Extraordinary new commercially available methods will make the screening procedures proposed practical, feasible and affordable. If our hypothesis is correct and we demonstrate EBNA2-dependent mechanisms of gene regulation at the risk loci, then these would be nominated as potential causal mechanisms for the genesis of SLE. These results will lay the foundation for the important next step, to perturb the identified mechanism in ways that change the risk of developing SLE or that change the capacity of the illness to persist.